Fracture Patterns and Mortality in Osteopetrosis: A 7-year Retrospective Analysis from Türkiye's National Registry.

BACKGROUND: The aim of this study is to determine the demographic data, fracture treatment methods, and medical treatments of patients diagnosed with osteopetrosis in the national registry. METHODS: Patients with International Classification of Diseases (ICD)-10 code Q78.2 for osteopetrosis between January 1, 2016 and April 11, 2023 were retrospectively reviewed. Data on sex, age at time of diagnosis, fracture history, mortality, and use of medications were evaluated for all patients. In addition, open reduction and internal fixation, closed reduction and internal fixation, closed reduction and casting, and conservative treatment methods were noted. The number of patients requiring deformity surgery was determined. The incidence and prevalence of osteopetrosis were also calculated in this cross-sectional study. RESULTS: A total of 476 patients diagnosed with osteopetrosis were identified. The mean age at time of diagnosis of these patients was 5.79 ± 5.43 years. A total of 101 patients died. As the age at diagnosis decreased, the mortality rate of the patients increased with statistical significance ( P <0.001). A total of 192 fractures were seen in 121 osteopetrosis patients in this study. Femur fractures were most common among these patients with osteopetrosis. A history of fracture was statistically significantly less common in patients using a combination of vitamin D + calcium compared with patients not using such medication ( P <0.001). In this 7-year cross-sectional study, the incidence was found to be 1 in 416,000 and the prevalence was 0.00199% in the population under 18 years of age. CONCLUSION: Younger age at diagnosis is associated with higher mortality in patients with osteopetrosis. In addition, the combination of vitamin D and calcium were associated with lower fracture incidence. LEVEL OF EVIDENCE: Prognostic Level II.

Total Hip Arthroplasty in Patients With Osteopetrosis.

BACKGROUND: Osteopetrosis is an inherited bone disease associated with high risk of osteoarthritis and fracture non-union, which can lead to total hip arthroplasty (THA). Bone quality and morphology are altered in these patients, and there are limited data on results of THA in these patients. The goals of this study were to describe implant survivorship, clinical outcomes, radiographic results, and complications in patients with osteopetrosis undergoing primary THA. METHODS: We identified 7 patients (9 hips) with osteopetrosis who underwent primary THA between 1970 and 2017 utilizing our total joint registry. The mean age at index THA was 48 years and included two males and five females. The mean follow-up was 8 years. RESULTS: The 10-year survivorship free from any revision or implant removal was 89%, with 1 revision and 1 resection arthroplasty secondary to periprosthetic femoral fractures. The 10-year survivorship free from any reoperation was 42%, with 4 additional reoperations (2 ORIFs for periprosthetic femoral fractures, 1 sciatic nerve palsy lysis of adhesions, 1 hematoma evacuation). Harris hip scores significantly increased at 5 years (P = .04). Five hips had an intraoperative acetabular fracture, and 1 had an intraoperative femur fracture. All postoperative femoral fractures occurred in patients with intramedullary diameter less than 5 mm at a level 10 cm distal to the lesser trochanter. CONCLUSION: Primary THA in patients with osteopetrosis is associated with good 10-year implant survivorship (89%), but a very high reoperation (58%) and periprosthetic femoral fracture rate (44%). Femoral fractures appear associated with smaller intramedullary diameters.

The evolving therapeutic landscape of genetic skeletal disorders.

BACKGROUND: Rare bone diseases account for 5% of all birth defects yet very few have personalised treatments. Developments in genetic diagnosis, molecular techniques and treatment technologies however, are leading to unparalleled therapeutic advance. This review explores the evolving therapeutic landscape of genetic skeletal disorders (GSDs); the key conditions and there key differentials. METHODS: A retrospective literature based review was conducted in December 2018 using a systematic search strategy for relevant articles and trials in Pubmed and clinicaltrials.gov respectively. Over 140 articles and 80 trials were generated for review. RESULTS: Over 20 personalised therapies are discussed in addition to several novel disease modifying treatments in over 25 GSDs. Treatments discussed are at different stages from preclinical studies to clinical trials and approved drugs, including; Burosumab for X-linked hypophosphatemia, Palovarotene for Hereditary Multiple Exostoses, Carbamazepine for Metaphyseal Chondrodysplasia (Schmid type), Lithium carbonate and anti-sclerostin therapy for Osteoporosis Pseudoglioma syndrome and novel therapies for Osteopetrosis. We also discuss therapeutic advances in Achondroplasia, Osteogenesis Imperfecta (OI), Hypophosphotasia (HPP), Fibrodysplasia Ossificans Progressiva, and RNA silencing therapies in preclinical studies for OI and HPP. DISCUSSION: It is an exciting time for GSD therapies despite the challenges of drug development in rare diseases. In discussing emerging therapies, we explore novel approaches to drug development from drug repurposing to in-utero stem cell transplants. We highlight the improved understanding of bone pathophysiology, genetic pathways and challenges of developing gene therapies for GSDs.

High bone mass in adults.

A finding of high bone mineral density (BMD) from routine dual-energy X-ray absorptiometry (DXA) screening is not uncommon. No consensus exists about the definition of high BMD, and T-score and/or Z-score cutoffs of ≥+2.5 or ≥+4 have been suggested. The many disorders that can result in high BMD are usually classified based on whether the BMD changes are focal vs. generalized or acquired vs. constitutional. In over half the cases, careful interpretation of the DXA report and images identifies the cause as an artefact (e.g., degenerative spinal disease, vascular calcifications, or syndesmophytes) or focal lesion (e.g., sclerotic bone metastasis or Paget's disease). Generalized acquired high BMD may be secondary to a diverse range of disorders such as fluorosis, diffuse bone sclerosis related to renal osteodystrophy, hematological diseases, and hepatitis C. Identification of the cause may require additional investigations such as imaging studies, serum tryptase assay, or serological tests for the hepatitis C virus. Finally, high BMD is a feature of many genetic diseases, most notably osteopetrosis and the disorders caused by mutations in the sclerostin gene SOST (sclerosing bone dysplasia and van Buchem disease) or in the LRP5 gene encoding the low-density lipoprotein receptor-related protein 5 (which is the Wnt co-receptor).

Diagnosis and Management of Osteopetrosis: Consensus Guidelines From the Osteopetrosis Working Group.

Background: Osteopetrosis encompasses a group of rare metabolic bone diseases characterized by impaired osteoclast activity or development, resulting in high bone mineral density. Existing guidelines focus on treatment of the severe infantile forms with hematopoietic cell transplantation (HCT) but do not address the management of patients with less severe forms for whom HCT is not the standard of care. Therefore, our objective was to develop expert consensus guidelines for the management of these patients. Methods: A modified Delphi method was used to build consensus among participants of the Osteopetrosis Working Group, with responses to an anonymous online survey used to identify areas of agreement and conflict and develop a follow-up survey. The strength of recommendations and quality of evidence was graded using the Grading of Recommendations Assessment, Development and Evaluation system. Results: Consensus was found in the areas of diagnosis, monitoring, and treatment. We recommend relying on characteristic radiographic findings to make the diagnosis and found that genetic testing adds important information by identifying mutations associated with unique disease complications. We recommend ongoing monitoring for changes in mineral metabolism and other complications, including cranial nerve impingement, anemia, leukopenia, and dental disease. We suggest that calcitriol should not be used in high doses and instead recommend symptom-based supportive therapy for disease complications because noninfantile osteopetrosis has no effective treatment. Conclusions: Scarcity of published studies on osteopetrosis reduce the ability to develop evidence-based guidelines for the management of these patients. Expert opinion-based guidelines for this rare condition are nevertheless important to enable improved care.

Osteopetrosis con afectación de cuatro nervios craneales / Osteopetrosis with damage of four cranial nerves

Introducción: la osteopetrosis se caracteriza por una insuficiente resorción ósea, como consecuencia de un trastorno de la actividad de los osteoclastos, y provoca aumento de la densidad ósea, es decir, un hueso altamente calcificado, pero muy frágil; hay fracaso del potencial de la médula ósea, desencadenando la hematopoyesis secundaria, con manifestaciones de visceromegalia y pancitopenia. El engrosamiento de los huesos provoca estrechamiento de los forámenes del cráneo, por donde emergen los nervios craneales, se comprimen y provoca manifestaciones clínicas secundariamente. Presentación del caso: paciente femenina que a los 3 años de edad manifestó nistagmus horizontal, paresia de nervio motor ocular externo derecho, pérdida de respuesta al estímulo auditivo bilateral, parálisis facial periférica izquierda y atrofia bilateral del nervio óptico; radiológicamente mostró aumento de la densidad ósea, con importante engrosamiento de la base de cráneo y huesos largos. Conclusiones: el diagnóstico de la osteopetrosis es sencillo y depende principalmente de los estudios radiológicos, pero pasa inadvertido por su baja frecuencia y falta de sospecha clínica. El diagnóstico temprano del compromiso de múltiples nervios craneales, la atención multidisciplinaria y su tratamiento oportuno, contribuye a su mejor evolución(AU)

Introduction: osteopetrosis is characterized by insufficient bone resorption as a consequence of a disorder in the osteoclast activity and brings about increased bone density, that is, a highly calcified bone but very fragile. There is failed potential of the bone marrow, thus unleashing secondary hematopoiesis with visceromegalia and pancitopenia manifestations. The bone thickening provokes narrowing in cranium foramens where the cranial nerves pass, they compressed and cause secondary clinical manifestations. Case report: a female patient aged 3 years showed horizontal nistagmus, paresia in the right external ocular motor nerve, loss of response to bilateral hearing stimulus, peripheral facial palsy and bilateral atrophy of the optical nerve. The radiological tests showed increased bone density with significant thickening of the skull base and long bones. Conclusions: the diagnosis of osteopetrosis is simple and mainly depends on the radiological studies, but it is unnoticed because of its low frequency and the inexistent clinical suspicion. The early diagnosis of the damage of several cranial nerves, the multidisciplinary care and timely treatment may contribute to better evolution(AU)

Bone mineral density and inflammatory and bone biomarkers after darunavir-ritonavir combined with either raltegravir or tenofovir-emtricitabine in antiretroviral-naive adults with HIV-1: a substudy of the NEAT001/ANRS143 randomised trial.

BACKGROUND: Osteopenia, osteoporosis, and low bone mineral density are frequent in patients with HIV. We assessed the 96 week loss of bone mineral density associated with a nucleoside or nucleotide reverse transcriptase inhibitor (NtRTI)-sparing regimen. METHODS: Antiretroviral-naive adults with HIV were enrolled in 78 clinical sites in 15 European countries into a randomised (1:1), open-label, non-inferiority trial (NEAT001/ANRS143) assessing the efficacy and safety of darunavir (800 mg once per day) and ritonavir (100 mg once per day) plus either raltegravir (400 mg twice per day; NtRTI-sparing regimen) or tenofovir (245 mg once per day) and emtricitabine (200 mg once per day; standard regimen). For this bone-health substudy, 20 of the original sites in six countries participated, and any patient enrolled at one of these sites who met the following criteria was eligible: plasma viral loads greater than 1000 HIV RNA copies per mL and CD4 cell counts of fewer than 500 cells per µL, except in those with symptomatic HIV infection. Exclusion criteria included treatment for malignant disease, testing positive for hepatitis B virus surface antigen, pregnancy, creatinine clearance less than 60 mL per min, treatment for osteoporosis, systemic steroids, or oestrogen-replacement therapy. The two primary endpoints were the mean percentage changes in lumbar spine and total hip bone mineral density at week 48, assessed by dual energy x-ray absorptiometry (DXA) scans. We did the analysis with an intention-to-treat-exposed approach with antiretroviral modifications ignored. The parent trial is registered with ClinicalTrials.gov, number NCT01066962, and is closed to new participants. FINDINGS: Between Aug 2, 2010, and April 18, 2011, we recruited 146 patients to the substudy, 70 assigned to the NtRTI-sparing regimen and 76 to the standard regimen. DXA data were available for 129, 121 and 107 patients at baseline, 48 and 96 weeks respectively. At week 48, the mean percentage loss in bone mineral density in the lumbar spine was greater in the standard group than in the NtRTI-sparing group (mean percentage change -2.49% vs -1.00%, mean percentage difference -1.49, 95% CI -2.94 to -0.04; p=0.046). Total hip bone mineral density loss was similarly greater at week 48 in the standard group than in the NtRTI-sparing group (mean percentage change -3.30% vs -0.73%; mean percentage difference -2.57, 95% CI -3.75 to -1.35; p<0.0001). Seven new fractures occurred during the trial (two in the NtRTI-sparing group and five in the standard group). INTERPRETATION: A raltegravir-based regimen was associated with significantly less loss of bone mineral density than a standard regimen containing tenofovir disoproxil fumarate, and might be a treatment option for patients at high risk of osteopenia or osteoporosis who are not suitable for NtRTIs such as abacavir or tenofovir alafenamide. FUNDING: The European Union Sixth Framework Programme, Inserm-ANRS, Ministerio de Sanidad y Asuntos Sociales de España, Gilead Sciences, Janssen Pharmaceuticals, and Merck Laboratories.

Osteopetrosis marmórea: reporte de un caso con esta rara enfermedad / Marble osteopetrosis: report of a case with this rare disease

Fundamento: la Osteopetrosis agrupa un conjunto de enfermedades óseas caracterizadas por aumento de la densidad ósea, debido a una disfunción osteoclástica. Se la conoce también como enfermedad marmórea o de Albers-Schönberg.Objetivo: realizar la presentación de un caso de osteopetrosis marmórea y la revisión del tema.Caso clínico: paciente de sexo masculino, de 14 años de edad. Sin antecedentes de consanguinidad de los padres, que acude por dolor óseo generalizado, que se irradiaba a lo largo de las extremidades, además de cefalea intensa que motivó estudio por neurología. En los estudios neurológicos resaltó la región mastoidea izquierda, por lo que se niega inflamaciones articulares, fiebre, erupción, nódulos, lesiones de piel. No existen elementos de hipoplasia medular asociada a la enfermedad en este paciente. En el examen físico actual no se evidencia hallazgo alguno de enfermedad inflamatoria crónica. Radiografías del paciente revelan un aumento generalizado de la densidad ósea, deformidades por desalineación, esclerosis ósea difusa, esto se traduce en huesos densos, anchos, sin canal medular, lo que representa cartílago hipermineralizado.Conclusiones: los estudios radiológicos fueron positivos y confirmaron el diagnóstico de la Osteopetrosis marmórea en la forma benigna; no es necesario el uso de otros estudios de imágenes para confirmarlo(AU)

Background: osteopetrosis includes a group of osseous diseases characterized by an increase of the bone density due to an osteoclastic dysfunction. It is also known as marble disease or Albers-Schönberg disease.Objective: to present a case with marble osteopetrosis and make the review of the topic.Clinical case: a fourteen-year-old male patient who presented bone pain that spread to the limbs, as well as severe headache that motivated a neurology study. A predominance of the left mastoid region denied the presence of articular inflammation, fever, rash, nodules or skin lesions. There were not elements of medullary hypoplasia associated to the disease of this patient. In the present physical examination no chronic disease was found. The x-rays of the patient show a widespread increase of the bone density, deformities caused by desalination and diffused bone sclerosis; all this means dense, broad bones without medullary channel which represents hypermineralized cartilages.Conclusions: the radiologic studies were positive and confirmed the diagnosis of marble osteopetrosis (benign). The use of other imaging studies was not necessary to confirm it(AU)

Forensic investigation of a 1986 outbreak of osteopetrosis in commercial brown layers reveals a novel avian leukosis virus-related genome.

Avian leukosis virus (ALV) is known to cause several neoplastic conditions in chickens, such as B-cell lymphomas, myelocytomas, erythroblastosis, and other types of neoplasia including osteopetrosis. We describe herein the identification of unique ALV-related proviral DNA sequences in an archived chicken bone affected with osteopetrosis. The osteopetrotic bone was obtained from an affected 46-week-old brown layer during an outbreak of osteopetrosis in Costa Rica in 1986. Analysis of proviral DNA in the 23-year-old osteopetrotic bone revealed unique exogenous ALV-related sequences that were named CR-1986 (Costa Rica, 1986). The 5' and 3' long terminal repeats (LTR) in the proviral DNA were identical to each other. The U3 regions in the LTRs were most similar to equivalent sequences in ALV-J, while U5 was identical to known endogenous ALV-E sequences. The predicted CR-1986 envelope protein was most similar to the envelope of myeloblastosis associated virus type 1 (MAV-1), although the percentage of amino acid sequence similarity to MAV-1 was low (90.4%). The variable and hypervariable regions of gp85 displayed several mutations compared to representative strains of ALV. The gp37 (transmembrane or TM) envelope protein showed three leucine to serine mutations that may represent important changes in the conformation of this protein, a finding that is currently being investigated. Several recombination events may have contributed to the emergence of CR-1986 because each analyzed segment was similar to a different ALV. CR-1986 may represent a unique ALV based on distinctive characteristics of its predicted envelope protein in comparison to previously reported ALVs.

Osteopetrosis del adulto. Conceptos actuales / Osteopetrosis of the adult. Current concepts

Se presentan cuatro casos de osteopetrosis del adulto, entidad poco frecuente, recogidos en nuestro hospital desde 1985 hasta 2005. Se revisa la patogenia y se actualizan conceptos y clasificación. Las manifestaciones clínicas se corresponden con otras publicaciones en las que la edad al diagnóstico es muy variable y el primer síntoma oscila desde dolor óseo a un hallazgo tras una fractura. Se revisan las mutaciones genéticas clásicas de todos los tipos, actualizando conceptos. Se introduce la propuesta de retirada de la osteopetrosis tipo I del adulto, ya que su patogenia parece un defecto intrínseco osteoblástico(AU)

We presents four cases of adult osteopetrosis, a very rare disease, compiled from our hospital from 1985 to 2005. Revising the pathogenesis and updating the current concept and classification. The clinical manifestations correspond with other publications where the age at diagnosis is highly variable and the first symptom oscillate from bone pain to a fracture. Presents the classic genetic mutations of all types updating concepts. Introducing the propose withdrawal of adult osteoporosis type I, because the pathogenesis seemed a intrinsic osteoblastic defect(AU)

Osteoporosis in adults with cerebral palsy.

Life expectancy for the 400 000 adults with cerebral palsy (CP) in the USA is increasing. Although there is a perception of increased fractured rate in the adult with CP, it has not been well studied. Low bone mineral density is found in more than 50% of adults with a variety of disabilities, including CP. Dual-energy X-ray absorptiometry scanning is commonly used to assess bone mineral density, but is limited by positioning and other artifacts in adults with CP. Novel scanning regions of interest, such as the distal femur, are not yet standardized in adults. Nutritional assessment and physical activity, the basis of most fracture prevention programs, are difficult to do in the adult with CP. A better understanding of the 'muscle-bone unit' physiology and its exploitation may lead to better treatment modifications. Clinical research trials with bisphosphonates (e.g. pamidronate), estrogen, selective estrogen receptor modulators, parathyroid hormone analogs, and growth hormone need to be targeted to the adult with CP. Longitudinal studies of fracture risk factors, genetic research in bone and neuromuscular biology, and the development of treatment surrogates for physical activity are additional areas of needed expertise. This could be facilitated by an adult CP registry and the centralization of clinical research efforts.

Osteopetrosis.

Osteopetrosis ("marble bone disease") is a descriptive term that refers to a group of rare, heritable disorders of the skeleton characterized by increased bone density on radiographs. The overall incidence of these conditions is difficult to estimate but autosomal recessive osteopetrosis (ARO) has an incidence of 1 in 250,000 births, and autosomal dominant osteopetrosis (ADO) has an incidence of 1 in 20,000 births. Osteopetrotic conditions vary greatly in their presentation and severity, ranging from neonatal onset with life-threatening complications such as bone marrow failure (e.g. classic or "malignant" ARO), to the incidental finding of osteopetrosis on radiographs (e.g. osteopoikilosis). Classic ARO is characterised by fractures, short stature, compressive neuropathies, hypocalcaemia with attendant tetanic seizures, and life-threatening pancytopaenia. The presence of primary neurodegeneration, mental retardation, skin and immune system involvement, or renal tubular acidosis may point to rarer osteopetrosis variants, whereas onset of primarily skeletal manifestations such as fractures and osteomyelitis in late childhood or adolescence is typical of ADO. Osteopetrosis is caused by failure of osteoclast development or function and mutations in at least 10 genes have been identified as causative in humans, accounting for 70% of all cases. These conditions can be inherited as autosomal recessive, dominant or X-linked traits with the most severe forms being autosomal recessive. Diagnosis is largely based on clinical and radiographic evaluation, confirmed by gene testing where applicable, and paves the way to understanding natural history, specific treatment where available, counselling regarding recurrence risks, and prenatal diagnosis in severe forms. Treatment of osteopetrotic conditions is largely symptomatic, although haematopoietic stem cell transplantation is employed for the most severe forms associated with bone marrow failure and currently offers the best chance of longer-term survival in this group. The severe infantile forms of osteopetrosis are associated with diminished life expectancy, with most untreated children dying in the first decade as a complication of bone marrow suppression. Life expectancy in the adult onset forms is normal. It is anticipated that further understanding of the molecular pathogenesis of these conditions will reveal new targets for pharmacotherapy.

Autosomal dominant osteopetrosis: clinical severity and natural history of 94 subjects with a chloride channel 7 gene mutation.

CONTEXT: Autosomal dominant osteopetrosis (ADO) is a sclerosing bone disorder caused by heterozygous mutations in the chloride channel 7 (ClCN7) gene. The clinical manifestations of this disease have not been well characterized since the discovery of the genetic basis of ADO. OBJECTIVES: The primary objectives were to improve our understanding of ADO clinical characteristics and to study the natural history of the disease in the largest series of patients reported to date. DESIGN AND SETTING: This study was primarily a retrospective cross-sectional analysis of individuals with a ClCN7 mutation that was conducted over a 4-yr period at a tertiary referral center and through family reunions. Longitudinal data on a subset of subjects were also studied. PATIENTS AND INTERVENTIONS: We studied 311 subjects from 11 ADO families, including 62 individuals with ADO (patients with the classic clinical phenotype based on radiographs and/or biochemistry), 32 unaffected gene carriers (subjects with the gene mutation but no radiographic and/or biochemical phenotype), and 217 controls who did not harbor a ClCN7 gene mutation. Clinical data were collected through patient interviews and examinations, medical records, and/or self-reported responses on a questionnaire that was completed by all subjects. MAIN OUTCOME MEASURES: The prevalence of fracture, osteomyelitis, visual loss, and bone marrow failure was determined. Differences in clinical manifestations were analyzed according to affected vs. carrier status, age, and underlying genotype. RESULTS: Ninety-two percent of ADO subjects had at least one sequela of the disease. Gene carriers did not have an increased risk of disease manifestations, although they were found to have significant increases in bone mineral density (P < 0.05). Compared with controls, subjects with ADO had a significantly increased prevalence of fracture (84 vs. 36%; P < 0.0001) and osteomyelitis (16 vs. 0.9%; P < 0.0001). Severe fractures (defined as > or =10 fractures of any type and/or greater than one hip/femur fracture) were identified only in ADO subjects, and osteomyelitis typically occurred in the maxilla or mandible in older adults. Visual loss, which typically had its onset in childhood, and bone marrow failure occurred in 19 and 3% of ADO subjects, respectively. Adults were more likely to manifest an ADO clinical characteristic, but no definitive genotype-phenotype relationship could be concluded. Longitudinal data suggest that the ADO clinical phenotype worsens over time. CONCLUSIONS: ADO caused by mutations in the CLCN7 gene is a frequently symptomatic disease manifested by a high rate of fracture, osteomyelitis, visual loss, and occasional bone marrow failure. The sequelae of ADO, which can be identified as early as infancy, appear to worsen over time. Fracture is the most prevalent consequence of ADO, although other more severe manifestations of disease can occur and should not be confused with recessive forms of osteopetrosis, particularly when identified in early childhood.

Association of an aromatase TTTA repeat polymorphism with circulating estrogen, bone structure, and biochemistry in older women.

Osteoporosis is a disease that is strongly genetically determined. Aromatase converts androgens to estradiol in postmenopausal women, therefore polymorphisms of the gene for this enzyme may be associated with bone mass and fracture. We investigated the association of the TTTA microsatellite polymorphism in intron 4 of the aromatase (CYP19) gene with bone mineral density (BMD) and fracture in 1,257 women aged 70 yr and greater. The data obtained were stratified based on the presence or absence of a [TTTA]n of 7 (A2), determined from a preliminary analysis of hip dual-energy X-ray absorptiometry BMD, which was present in 27% of the population. The presence of an A2 allele was associated with a higher free estradiol index (0.52 +/- 0.49, P = 0.049) compared with the absence of an A2 allele (0.47 +/- 0.45); higher BMD at all sites of the hip (3.4% total hip, 2.3% femoral neck, 3.6% intertrochanter, 4.1% trochanter) and the lumbar spine (12.7%); higher values for the calcaneal quantitative ultrasound parameters broadband ultrasound (1.3%), speed of sound (0.4%), and stiffness (3.7%); and higher peripheral quantitative computed tomography measures for total (3.4%), trabecular (3.3%), and cortical BMD (3.3%) and the derived stress strain index (SSI) parameters SSI polar (6.4%) and SSI x (6.8%) values. A lower deoxypryridinoline creatinine ratio was observed in subjects with an A2 allele (30.3 +/- 10.4 vs. 27.1 +/- 9.1, P = 0.03). The A2 allele was associated with a lower prevalence of vertebral fracture in subjects who were osteoporotic (odds ratio 0.27, confidence interval 0.09-0.79). Therefore, a common polymorphism of the aromatase gene, perhaps in linkage disequilibrium with a functionally significant CYP19 polymorphism, is associated with bone structure and bone turnover, either by local effects or by effects on circulating bioactive estrogen.

Osteoclast diseases.

Osteoclasts are the only cells capable of resorbing mineralised bone, dentine and cartilage. Osteoclasts act in close concert with bone forming osteoblasts to model the skeleton during embryogenesis and to remodel it during later life. A number of inherited human conditions are known that are primarily caused by a defect in osteoclasts. Most of these are rare monogenic disorders, but others, such as the more common Paget's disease, are complex diseases, where genetic and environmental factors combine to result in the abnormal osteoclast phenotype. Where the genetic defect gives rise to ineffective osteoclasts, such as in osteopetrosis and pycnodysostosis, the result is the presence of too much bone. However, the phenotype in many osteoclast diseases is a combination of osteosclerosis with osteolytic lesions. In such conditions, the primary defect is hyperactivity of osteoclasts, compensated by a secondary increase in osteoblast activity. Rapid progress has been made in recent years in the identification of the causative genes and in the understanding of the biological role of the proteins encoded. This review discusses the known osteoclast diseases with particular emphasis on the genetic causes and the resulting osteoclast phenotype. These human diseases highlight the critical importance of specific proteins or signalling pathways in osteoclasts.

[Autosomal-dominant osteopetrosis in Chuvashiya]. / Autosomno-dominantnyi osteopetroz v Chuvashii.

A genetic epidemiological study of osteopetrosis was carried out in Chuvashiya. The major signs of this disorder are severe anemia developed in the prenatal or early postnatal life, hepatosplenomegaly, and a progressive loss of sight and hearing. Osteopetrosis showed the autosomal recessive inheritance with a somewhat increased proportion of affected patients in families. The lowest estimate of osteopetrosis frequency in Chuvashiya was 0.00026, one affected patient per 3879 newborns. The osteopetrosis gene occurred at a frequency of 0.016; the proportion of heterozygotes was 3.15%. The gene was shown to be evenly distributed throughout the republic.

[Recessive osteopetrosis. Identification of a form of medium severity]. / La forme récessive de l'ostéopétrose. Individualisation d'une forme de gravité intermédiaire.

BACKGROUND: Several distinct forms of osteopetrosis have been identified. Some of the autosomally recessive inherited forms are benign, much like the autosomal dominant form. Others are more malignant. PATIENTS: The clinical data, skeletal radiographs, histological features and histories of 32 children with osteopetrosis were analyzed retrospectively. RESULTS: The 32 patients, belonging to 20 sibships were divided into two groups. The first group included 24 patients, aged 1 day-11 months (mean 4.5 months), suffering from hepatosplenomegaly, anemia, thrombocytopenia and optic atrophy in early infancy. They also had a generalized increase in bone density, abnormal bone remodeling, rachitic lesions and a "bone-within-bone" appearance. Biopsies showed severe bone resorption and myelofibrosis. 19 of the 20 patients whose outcomes were known died during the first year of life. The second group included 8 patients, aged 40 days-3 years (mean: 11 months). Hepatosplenomegaly appeared later, anemia was less severe and thrombocytopenia occurred in only 1 patient. However, all 8 patients suffered from optic atrophy and 3 were deaf. Radiographs showed bone growth without rachitic lesions. Biopsies from 2 patients showed bone resorption, but no myelofibrosis. The outcome was less severe: 6 patients, now aged 8 months to 8 years, have survived, 3 of them for over 5 years. Genetic investigation showed patterns compatible with autosomal recessive inheritance in both groups, with similar sets of features within each sibship. CONCLUSION: This study reveals a new type of recessively inherited osteopetrosis. It can be classified as an intermediate form, distinct from both the malignant and the benign forms, and also distinct from osteopetrosis with carbonic anhydrase II deficiency.